S-dkubstituted j-aminohydantoins



United States Patent 5,5-DISUBSTITUTED 3-AMINOHYDANTOINS William Taub,Rehovoth, Israel, assignor to J. R. Geigy A. G., Basel, Switzerland, aSwiss firm No Drawing. Application February 14, 1955, Serial No. 488,141

Claims priority, application Israel February 16, 1954 7 Claims. (Cl.260-3095) This invention relates to new pharmacologically activecompounds, namely 5.5-disubstituted 3-aminohydantoins of the generalformula:

122 NH-CO in which R1 and R2 stand for the same or different hydrocarbonradicals.

In particular, it has been found that these compounds have a pronounceddiuretic elfect.

The new compounds can be prepared for example by heating in an aqueoussuspension or solution a dihydrazide of the general formula:

Rz NHCONH-NHg wherein R1 and R2 have the meanings given above.

In this process, a large part of the Water can gradually be distilledofi to enable the liberated hydrazine to be continually removed. Thedihydrazides necessary are obtained, for example by heating diesters ofC.C-disubstituted glycine-N-carboxylic acids with excess hydrazine inalcoholic solution.

In another mode of performing the process, esters of monohydrazides ofC.Cdisubstituted glycine-N-carboxylic acids are heated until the hydroxycompound present in ester linkage is completely split off. Themonohydrazide esters of C.C-disubstituted glycine-N-carboxylic acidswhich serve as starting materials for these two processes are obtained,e. g. by reacting the corresponding diesters with hydrazine in alcoholicsolution at room temperature or at a moderately raised temperature.

The diesters of C.C-disubstituted glycine-N-carboxylic acids alreadymentioned as starting materials for the dihydrazides used for ringclosure can be obtained for example by reactions known per so fromketones of the general formula: R1CO-Rz, so that ketones which areeasily accessible are the basic materials for many of the disubstituted3-aminohydantoins according to the present invention. Such ketones can,for example, first be converted into the nitriles of C.C-disubstitutedglycines and these then converted into the corresponding esters. Onreacting these esters with chloroformic acid esters, the desireddiesters of C.C-disubstituted glycine-N-carboxylic acid are produced.Esters of C.C-disubstituted glycines can also be obtained by methodsknown per se (see, for example Org. Synth. 20, 42) by converting ketonesinto the corresponding hydantoins, splitting these and then esterifyingthe amino acids obtained.

In the production of the direct starting materials for such5.5-disubstituted 3-aminohydantoins which do not correspond to easilyobtainable ketones R1-CO-R2, the Hofmann degradation of C.Cdisubstitutedcyanaceta- 2,767,193 7 Patented Oct. 16, 1956 mides. according to Errerayielding disubstituted hydantoins by ring closure is a further possiblereaction which offers numerous variations with regard to the radicals R1and R2. Other possible ways of producing the starting materials can be.found from other syntheses described in the literature for theproduction of a-amino acids.

The following examples serve to illustrate the inven tion furtherwithout limiting it in any way. Parts are given as parts by weight.Where not otherwise mentioned, the relationship of parts by weight toparts by volume is as that of grammes to cubic centimetres. Thetemperatures are in degrees centigrade.

Example 1 A solution of 20.3 parts of N-carbethoxy-waminoisobutyric acidethyl ester and 50 parts of hydrazine hydrate in 200 parts by volume ofabsolute ethanol is refluxed for 20 hours. The alcohol is evaporated,the residue is dissolved in 500 parts of distilled water, and thesolution is concentrated by evaporation under ordinary pressure untilthe volume is reduced to about 50 parts by volume. Upon cooling,5.5-dimethyl-3-aminohydantoin crystallises in colourless crystals. Afterrecrystallisation from water, this compound melts at 184.

Example 2 Example 3 A solution of 23.1 parts ofN-carbethoxy-a-amino-aethyl butyric acid ethyl ester (B. P.21 mm.138-140") and 50 parts of hydrazine hydrate in 200 parts by volume ofabsolute ethanol is refluxed for 30 hours. Then the alcohol isevaporated, the residue is suspended in 500 parts of distilled water andthe solution is concentrated by evaporation under ordinary pressureuntil the volume is reduced to about 50 parts by volume. Upon cooling,5.5-diethyl-3-aminohydantoin crystallises in colourless crystals. Uponrecrystallisation from diluted ethanol this compound melts at 178-180".

Example 4 A solution of 25.9 parts of N-carbethoxy-a-arnino-abutylbutyric acid ethyl ester (B. P.2o mm. -162) and 50 parts of hydrazinehydrate in 200 parts by volume of absolute ethanol is refluxed for 20hours. Then the alcohol is evaporated, the residue is suspended in 500parts of distilled water and the solution is concentrated by evaporationunder ordinary pressure until the volume is reduced to about 70 parts byvolume. Upon cooling,

5-ethyl-5-n-butyl-3-aminohydantoin crystallises in colourless crystalswhich, upon recrystallisation from water, melt at 143-144".

Example 5 A solution of 27.3 parts ofN-carbethoxy-a-n-hexyl-aamino-propionic acid ethyl ester (B. R22 mm.180-181) and 65 parts of hydrazine hydrate in parts by volume ofabsolute methanol is refluxed for 30 hours. Then the solvent isevaporated: the residue is suspended in 750 parts of distilled water,and the solution is concentrated byevaporation under atmosphericpressure until the volume is reduced to about 55 parts by volume. Uponcooling, 5-methyl-5-n-hexyl-3-aminohydantoin crystallises in colourlesscrystals, Upon recrystallisation from ethanol, the new compound melts at136.

v Example 6 V A solution of 23.9 parts of N-carbomethoxy-u-amino-d-'benzyl'p'ropionic acid methyl ester (M. P. 45) or 2 6.7

parts of N-carbethoxy-u-amino-a-benzyl propionic acid ethyl ester and 60parts of" hydrazine hydrate in 200 parts" by volume of absolute ethanolare boiled under reflux for "30 hours. After'evaporating the solvent,the residue 'issuspended in 1000 parts by volume of water andthe volumeis reduced to about 80 parts by volume by evaporating oil? the waterunder normal pressure. After cooling, the precipitated-methyl-5-benzyl-3-aminohydantoin is filtered off and recrystallisedfrom ethanol. The following compounds 'canbe prepared in an analogousmanner:

touthe formula:

7 R1 QoNH-NH2 m NH-OO wherein R1 represents a hydrocarbon radical withat.

most 7. carbon atoms, and R2 represents a lower alkyl radical.

I 2. therapeutically active compound corresponding 7 to the formula:

0 o -Nn Nug wherein R1 and R2 each represents alower alkyl radical.

3fA th 'e'rapeutically active compound corresponding tofthe formula: 7

CH3 CONHNH2 4. A therapeutically active compound corresponding to theformula:

5. A therapeutically active compound corresponding to the formula:

02115 oo-mn-Nm n O4 Ht NHGO 6. A therapeutically active compoundcorresponding to the formula: 7 v V 02m. ,CO.NHNH2 l ll-05H NHCH 7. Atherapeutically active compound corresponding to the formula: V

0 2H; 0 O -NHNH2 cyclohexenyl NH-CO No references cited.

2. A THERAPEUTICALLY ACTIVE COMPOUND CORRESPONDING TO THE FORMULA: